PROJECT SUMMARY The candidate's long-term career goal is to become an independent investigator in the field of immune- associated diseases, with a focus on molecular mechanisms underlying sexual dimorphisms in immune disorders. Towards this goal, the career development plan will develop research and professional skills through a combination of research experience, clinical immersion, coursework, and additional professional training activities; all under the mentorship of an interdisciplinary group of experts.Specifically, it focuses on training in: 1) molecular aspects of cutaneous inflammation; 2) animal models for inflammatory and autoimmune diseases; 3) clinical aspects of autoimmune diseases; and 4) communication, collaboration, teaching, writing, and additional faculty skills. In addition, the completion of the research project in the career development plan will lay the scientific groundwork for the candidate's future research. The research project is summarized below: Sex disparity in the manifestation of immune diseases represents one of the most remarkable and unexplained examples of the biological differences between men and women. Many autoimmune diseases feature strikingly increased prevalence in females (e.g. systemic lupus erythematosus[SLE], female-to-male ratio 9:1), whereas in contrast, infectious diseases affect more men than women. Our preliminary results suggest that interferon(IFN)-mediated immune responses, key events in host defense and inflammation, exhibit sexual dimorphisms in human keratinocytes in a sex-hormone independent manner. Consistently, the female human skin is biased towards increased expression of genes associated with autoimmune disease susceptibility. These genes are independent of sex-hormone regulation, and are regulated by VGLL3, a female-increased, putative transcription factor. VGLL3 promotes the expression of immune genes, including interferon-stimulated genes (ISGs), in a manner that is significantly associated with transcriptomic alterations present in multiple female-biased autoimmune diseases including lupus. This project aims to identify the molecular basis of sex dimorphisms in IFN responses by testing the hypothesis that higher levels of VGLL3 in females enable priming of ISGs towards sensitized interferon responses and/or delayed recovery from stimulation. To address this we propose the following specific aims: Aim 1. Determine sex disparities in transcriptional responses to IFNs and their regulation by VGLL3 Aim 2. Establish the chromatin mechanism for sex-dependent ISG profiles Aim 3.Determine the in vivo role of VGLL3 in regulating IFN-mediated immune processes With the successful completion of this work, we will have made major advances towards understanding of the molecular basis for sex-dependent immunological processes. This work may also become the basis for novel, sex-specific therapeutic measures for infectious and autoimmune diseases.